Guanidine derivatives

Abstract

A compound of the formula:whereinR1 is hydrogen or halogen,R2 is hydroxy, acyl(lower)alkoxy, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, mono(or di or tri)halo(lower)alkyl, (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl, lower alkoxyimino(lower)alkyl, acyl, lower alkoxycarbonyl, carbamoyl, di(lower)alkylcarbamoyl, (amino(lower)alkyl)carbamoyl, N,N-di(lower)alkylamino(lower)alkylcarbamoyl, guanidinocarbonyl, morpholinylsulfonyl, sulfamoyl, lower alkylsulfamoyl, (lower alkylsulfonyl)(lower)alkyl, guanidinocarbonyl(lower)alkenyl, lower alkylthio, cyano, acyl(lower)alkyl, acyl(lower)alkenyl, aryl which has one or more substituent(s) or a heterocyclic group which has one or more substituent(s), andX is -O-, or a salt thereof.

What is claimed is:  
     
       1. A compound of the formula:                    
       wherein R 1  is hydrogen or halogen, 
       R 2  is hydroxy, acyl(lower)alkoxy, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, mono(or di or tri)halo(lower)alkyl, (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl, lower alkoxyimino(lower)alkyl, acyl, lower alkoxycarbonyl, carbamoyl, di(lower)alkylcarbamoyl, (amino(lower)alkyl)carbamoyl, N,N-di(lower)alkylamino(lower)alkylcarbamoyl, guanidinocarbonyl, morpholinylsulfonyl, sulfamoyl, lower alkylsulfamoyl, (lower alkylsulfonyl) (lower)alkyl, guanidinocarbonyl(lower)alkenyl, lower alkylthio, cyano, acyl(lower)alkyl, acyl(lower)alkenyl, aryl which has one or more substituent(s) or a heterocyclic group which has one or more substituent(s), and  
       X is —O—, or a salt thereof.  
     
     
       2. A compound of  claim 1 , 
       R 1  is hydrogen or halogen,  
       R 2  is hydroxy, lower alkoxycarbonyl(lower)alkoxy, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, dihalo(lower)alkyl, trihalo(lower)alkyl, (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl, lower alkoxyimino(lower)alkyl, carboxy, lower alkoxycarbonyl, carbamoyl, di(lower)alkylcarbamoyl, (amino(lower)alkyl)carbamoyl, N,N-di(lower)alkylamino(lower)alkylcarbamoyl, guanidinocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, morpholinylsulfonyl, sulfamoyl, lower alkylsulfamoyl, lower alkylthio, cyano, (lower alkylsulfonyl) (lower)alkyl, carboxy(lower)alkenyl, guanidinocarbonyl(lower)alkenyl, phenyl, which has one to four hydroxy(lower)alkyl substituents, thienyl which has one to three halogen substituents, or pyrrolidinyl which has one to four oxo substituents, and  
       X is —O—.  
     
     
       3. A compound of  claim 2 , 
       wherein 
       R 1  is hydrogen or halogen, and  
       R 2  is guanidinocarbonyl or lower alkylsulfonyl.  
     
     
       4. A compound of  claim 3 , which is selected from the group consisting of: 
       (1) (2,3-Dihydro-9-methanesulfonyl-1-benzoxepin-4-carbonyl)guanidine or its hydrochloride or methanesulfonate,  
       (2) (2,3-Dihydro-7-chloro-9-methanesulfonyl-1-benzoxepin-4-carbonyl)guanidine, and  
       (3) (2,3-Dihydro-9-guanidinocarbonyl-1-benzoxepin-4-carbonyl)guanidine or its dihydrochloride.  
     
     
       5. A pharmaceutical composition which comprises, as an active ingredient, a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers. 
     
     
       6. A method for inhibiting Na + /H +  exchange in cells comprising: 
       administering to a patient in need thereof an amount of a compound of  claim 1  effective to inhibit Na + /H +  exchange.  
     
     
       7. A method for treatment of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis or shock which comprises administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof to a human being or animal.